Myeloid Suppressor Cell-Mediated Immune Suppression of Tumor Specific T Cells

描述（由申请人提供）：越来越多的证据表明，具有抑制性表型的宿主免疫细胞对癌症的成功免疫增强治疗构成了重大障碍。在抑制细胞中，调节性T细胞（TCFs）和髓源性抑制细胞（MDSC）已被证明在晚期恶性肿瘤宿主中显著增加。先前，我们发现各种癌的生长诱导肿瘤、脾和骨髓中MDSC和Treg数量的显著增加。更有趣的是，我们已经证明，MDSC可以介导抑制肿瘤特异性T细胞反应，通过诱导T细胞无能和发展的Treg荷瘤小鼠。这些结果为MDSC和Treg在荷瘤宿主中的体内免疫抑制功能提供了强有力的证据。为了获得持久的抗肿瘤免疫，提高免疫调节治疗的疗效，必须研究和克服肿瘤诱导的免疫抑制。我们的研究表明，通过使用小分子抑制剂（苹果酸舒尼替尼; Sutent（r））靶向药理学破坏酪氨酸激酶信号传导可以防止MDSC的积累和Treg的抑制活性，从而提高基于免疫的治疗的功效。我们已经发现，调节肿瘤微环境中的炎症反应与免疫抑制所需的白细胞亚群可以通过舒尼替尼治疗来调节。我们假设受体酪氨酸激酶激活途径的破坏不仅可以逆转Treg抑制功能和Foxp 3基因表达，而且还可以刺激Th 17和Th 1炎症反应。将追求三个具体目标：1）研究酪氨酸激酶抑制剂（TKI）在体外和体内对Treg信号传导和功能的调节作用的分子机制; 2）研究TKI对Treg转化为Th 17和/或Th 1的作用; 3）研究TKI对人Treg和TKI治疗的癌症患者的作用，以及潜在的分子机制。苹果酸舒尼替尼作用的细胞和分子机制研究对于未来的临床转化至关重要。这些研究的成功完成将使我们更好地理解舒尼替尼改变肿瘤微环境和导致免疫转换的作用机制，并可能发现新的特异性靶点，可用于对抗与晚期恶性肿瘤相关的免疫抑制。免疫抑制的消除应显著增强用于治疗晚期转移性癌症的现有基于免疫的疗法的功效。 公共卫生相关性：本项目的目标包括：1）确定Sutent在CD 4 + CD 25 + FoxP 3 + T调节细胞中的直接靶点和调节机制; 2）确定与Sutent作用相似或更强的酪氨酸激酶抑制剂; 3）研究Sutent介导的T调节细胞向其他CD 4谱系转化的机制; 4）研究索坦对肿瘤患者调节性T细胞的影响。

DESCRIPTION (provided by applicant): A growing body of evidence suggests that host immune cells with a suppressive phenotype pose a significant hurdle to successful immune enhancing therapy for cancer. Among the suppressor cells, T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) have been shown to increase significantly in hosts with advanced malignancies. Previously, we found that the growth of various carcinomas induced a significant increase in the numbers of MDSC and Treg in tumor, spleen, and bone marrow. More interestingly, we have demonstrated that MDSC can mediate suppression of the tumor-specific T-cell response through the induction of T-cell anergy and the development of Treg in tumor-bearing mice. These results provide strong evidence of the in vivo immune suppressive functions of MDSC and Treg in tumor-bearing host. To achieve persistent anti-tumor immunity and to improve the efficacy of immunomodulatory therapy, tumor-induced immune suppression must be investigated and overcome. Our studies indicate that targeted pharmacological disruption of tyrosine kinase signaling through the use of a small molecule inhibitor (sunitinib malate; Sutent(r)) can prevent the accumulation of MDSCs and the suppressive activity of Treg, thereby improving the efficacy of immune-based therapy. We have found that leukocyte subsets required for the regulation of inflammatory response vs. immune suppression in the tumor microenvironment can be modulated by sunitinib treatment. We hypothesize that disruption of the receptor tyrosine kinase activation pathway may not only revert Treg suppressive function and Foxp3 gene expression but also stimulate Th17 and Th1 inflammatory responses. Three specific aims will be pursued: 1) To study the molecular mechanisms underlying the regulatory effect of tyrosine kinase inhibitors (TKIs) on Treg signaling and function in vitro and in vivo; 2) To study the effect of TKI on the conversion of Treg into Th17 and/or Th1; 3) To study the effect of TKI, on human Treg and in TKI treated cancer patients, and the underlying molecular mechanisms. Studies of the cellular and molecular mechanisms of action utilized by sunitinib malate are critically important for future clinical translation. Successful completion of these studies will result in a better understanding of the mechanisms of action employed by sunitinib to alter the tumor microenvironment and result in immune conversion and may lead to the discovery of novel and specific targets that can be used to combat the immune suppression associated with advanced malignancies. The ablation of immune suppression should significantly augment the efficacy of existing immune-based therapies for treatment of advanced metastatic cancer. PUBLIC HEALTH RELEVANCE: The goal of this project includes 1) Identify the direct targets and regulation mechanisms of Sutent in CD4+CD25+FoxP3+ T regulatory cells; 2) Identify tyrosine kinase inhibitors that have a similar or stronger effect than Sutent; 3) Study the mechanisms underlying the conversion of T regulatory cells to other CD4 lineages mediated by Sutent; 4) Study the effect of Sutent on human T regulatory cells in cancer patients.